The characterization of cognitive impairment in older adults, and particularly those at risk for Alzheimer's disease (AD) is critically important. The most widely identified risk factors for AD are increasing age and the presence of the apolipoprotein E epsilon 4 allele. In order to delay age of AD onset and improve quality of life, it is important to identify cognitive changes in older adults as early as possible. The detection of early indicators of AD could reduce the cost of AD care by as much $100 billion per year in the U.S. and interventions that delay AD onset by two years could result in nearly two million fewer cases in 50 years. Therefore, the primary aim of this proposal is to use an innovative, process-oriented approach to examine deficits in specific mnemonic processes in older adults at risk for AD. Impaired episodic memory is regarded as a hallmark deficit in older adults and may serve as an early indicator of AD. The accurate encoding and retrieval of one episodic memory from another may require the function of multiple mnemonic processes to associate the elements of an episodic memory together and also separate the elements from those belonging to a different memory to avoid catastrophic interference. Although episodic memory may involve various cortical regions, there is strong evidence that the hippocampus plays a critical role in supporting specific mnemonic processes such as pattern separation and the formation of arbitrary associations that may enhance episodic memory accuracy. Despite overwhelming evidence suggesting that hippocampal pathology is highly associated with aging, studies have not adequately examined these specific memory processes in older adults at risk for AD. The proposed experiments are highly significant because behavioral tasks that measure these specific mnemonic processes may be powerful and largely unexamined tools for the early detection of age-related cognitive dysfunction. Disruption of these processes may result in impairments in various cognitive functions critical to the execution of daily living skills. The identification of key mnemonic processing deficits may result in behavioral interventions that structure daily living tasks to mitigate interference and enhance memory. Five novel experiments will be used in the proposed studies to provide a highly innovative investigation of specific memory processes in young adults and older adults at risk for AD. The aims of the grant will characterize age-related differences on the proposed experiments (Specific Aim 1), examine relationships between performance on the experiments and standardized neuropsychological tests (Specific Aim 2), and characterize the performance of older adults, with and without the APOE E4 allele on the experiments (Specific Aim 3). If the innovative aims of the present grant are achieved, novel behavioral approaches and methodologies will be developed for future aging studies investigating: 1) episodic memory impairment, 2) hippocampal subregion specific epigenetic and transcriptional changes, 3) structural and functional hippocampal changes using neuroimaging, and 4) the differentiation of preclinical markers of AD from those of normal aging. PUBLIC HEALTH RELEVANCE: Since increasing age is a widely identified risk factor for Alzheimer's disease (AD), the characterization of age-related cognitive impairment is critically important and could have profound social and financial implications by reducing the cost of care by as much $100 billion per year in the United States. The use of tasks that measure specific mnemonic processes such as pattern separation and arbitrary association formation that are critical to episodic memory, and known to be dependent on specific subregions of the hippocampus, may help to differentiate early markers of AD onset during the preclinical stages from those associated with normal aging. An investigation of tasks requiring these specific mnemonic processes may reveal powerful and largely unexamined tools for identifying age-related memory dysfunction that may result in catastrophic impairments in cognitive processes that are critical to the execution of daily living skills, and the findings may result in behavioral interventions that structure daily living tasks to improve memory function in older adults, increase functional independence, and reduce health care costs associated with aging.